The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines.

1. Rheumatoid arthritis (RA) is probably the most common source of treatable disability. A major problem in modern rheumatology is that the mechanism(s) of action of the currently used disease-modifying antirheumatic drugs (DMARDs) remain unclear. Many of these drugs entered rheumatology mainly through clinical intuition and have been used for decades. 2. The former T-cell-centered paradigm of rheumatoid inflammation has given way to a model of inflammation highlighting the macrophage and its proinflammatory cytokines. In particular, tumor necrosis factor alpha (TNF-alpha) has gained prominence as a central proinflammatory mediator in RA, and antibodies against TNF-alpha have been successfully used in patients with RA. 3. This review will summarize the recent advances in determining the mechanisms of action of the currently used DMARDs, with particular emphasis on their effects on the induction of TNF-alpha and interleukin 1 (IL-1) in mononuclear phagocytes. Although some DMARDs, such as auranofin, antimalarials and tenidap, act as inhibitors of the induction of these cytokines in monocytes or macrophages or both, other drugs, such as methotrexate, D-penicillamine and aurothiomalate, do not seem to affect either TNF-alpha or IL-1. 4. The drugs' effects on proinflammatory cytokine induction are correlated to those on other macrophage responses.